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Caffeine is the most widely consumed psychoactive substance with approximately 80% of the American population (adults and children) ingesting it on a regular basis[1] . It is a legal stimulant drug that affects the central nervous system and has well-recognized addictive properties [2] . Because of this and its high availability, the mechanisms through which it induces physical dependence (tolerance ) and triggers drug-seeking behavior are important to study.

Antagonism of adenosine receptors in the brain is the most likely mechanism through which caffeine exerts its effects under normal physiological conditions. The other mechanisms are significant only at higher caffeine plasma concentration not common in everyday use (see figure 1). Therefore, this neurowiki will focus on adenosine receptors inhibition by caffeine.

As a legal stimulant drug with well-recognized addictive properties [2], caffeine is a very available to the population at large and has the capacity to affect all age groups. It is therefore important to study its physiological effects and addictive potential in order to establish safety guidelines and recommendations for consumption. (For comparison, caffeine’s reinforcement properties are considerably weaker than those of other psychostimulant drugs but nevertheless significant [7].

1.2 Pharmacokinetics

Caffeine(chemical formula: 1,3,7-trimethylxanthine) crosses the blood brain barrier rapidly within minutes as its physiochemistry renders endothelial membranes freely permeable [8] . It is absorbed from the gut with 99% efficiency and has a half-life of 2.5 to 4.5 hr [9] but that gets reduced in smokers with up to 50% [10]. It takes 15 to 120 min for peak plasma concentration to be achieved [11]. Caffeine is broken down in the liver by CYP 450 enzymes before clearance [12].

1.4 Four mechanisms through which caffeine exerts its effects on the brain

2. Adenosine

2.1 Endogenous functions

Adenosine is a purine nucleoside acting as neuromodulator in the central nervous system. It is present in all cells but has receptors (adenosine receptors = AR) mainly on brain cells [27]. Adenosine has been referred to as the “signal of life” and “retaliatory metabolite” because it increases when a cell’s ATP demand increases its ATP synthesis to signal the cell to slow down its metabolic processes and restore energy balance [28]. Adenosine has many endogenous functions in the central nervous system (see figure3) but it is most widely known for its sleep-inducing effects and indeed supporting evidence for that claim exists as adenosine accumulates during wakefulness and starts to decrease with the onset of sleep [29]. It is also neuroprotective and increases during ischemic stress [30]. Adenosine limits the damage after ischemia-induced re-purfusion [31], can be used as anticonvulsant in epilepsy [32] and for relief of chronic pan [33] . It has also been demonstrated it can cause epigenetic changes by DNA methylation [34].

2.2 Synthesis in the brain

Adenosine de novo synthesis in the brain is insignificant [32] . Instead, it is mostly derived from ATP catabolism by AMP-selective 5`-nucleotidases (see figure 4 and 5). Amount synthesized is determined by ATP:AMP proportion, therefore reflecting the metabolic status of the cell.

Adenosine can be produced intracellularly or extracellularly (figure 5). Extracellular synthesis occurs after ATP secretion by astrocytes or neurons [35]. Ectonucleotidase (Ecto 5’NT on diagram) convert ATP to AMP and then to adenosine. Astroglia co-release ATP and glutamate onto striatal spines that co-express dopamine and AR (heterodimers of different types). Interestingly, astrocytes’ feet form the blood brain barrier and have A1 and A2A R that can regulate its permeability. This in turn renders control of nutrients in and out of the brain, as well as blood flow [36]. Intracellular synthesis occurs in astrocytes from ATP or from S -adenosylhomocysteine (SAH) via SAH hydrolase [37].

3. Adenosine Receptors

3.1 General structure

Four g-protein coupled receptor subtypes have been identified so far: A1, A2A, A2B, A3. All receptors activated have neuroprotective effects in the nervous system [33]. The general structure of the AR consists of a single polypeptide chain made up of 7 alpha helix transmembrane domains, intracellular C-terminal domain (with phosphorylation and palmitoylation sites important for desentisization and internalization) and extracellular N-terminal domain (with glycosylation sites) [38].

3.2 cAMP and AR activation

A1 and A3 subtypes activation results in Gi activation that inhibits adenylate cyclase activity and results in decrease of cAMP [32] . A2A and A2B, on the other hand, couple to Gs, Gq and G12, which leads to increase in cAMP. This in turn can activate PKA(cAMP dependent protein kinase A) which phosphorylates receptors and thus affects excitability of the neurons and their neurotransmitter release [39].

3.3 Downstream intracellular pathways

3.4 AR subtypes important in caffeine addiction

Affinity of adenosine for A1 and A2A is nearly equivalent and much higher than affinity for A2B and A3 [32]. Therefore caffeine antagonism is most likely to work through A1 and A2A receptor subtypes.

3.5 A1 AR

3.5.1 Effects of R stimulation – psychostimulant and motor activation

Knockout studies suggest A1 AR is important for psychostimulant effects of caffeine since antagonists to A1R subtype only produce caffeine – induced discriminative effects [40]. It has been suggested both A1 and A2A antagonism are responsible for motor activation produced by caffeine but only A1 antagonism results in discriminative effects [41].

It has been hypothesized that weaker pre-synaptic stimulation results in LTD instead of LTP due to A1 post-syn activation because in A1 knockout mice this LTD is not observed. Thus, post-synaptic A1 AR are likely to be important in plasticity[43].

3.5.3 A1 AR location in the brain (figure 8)

A1 AR are located throughout the brain, but more concentrated in the cortex, hippocampus and spinal cord [44].

3.6 A2A AR

A2A AR subtype is mostly synaptically localized in neurons with high concentration in the basal ganglia and olfactory tubercle [46]. It is also present at high density on endothelial cells of capillaries in the brain which renders control of microvasculature [47]. Activation has been demonstrated to cause vasodilation that subsequently improves oxygen and nutrient delivery to the brain tissue [48].

Like A1 subtype, A2A has been implicated in synaptic plasticity [49]. Generally this AR subtype exerts its effect by regulating neurotransmitter release or re-uptake. This is in contrast to A1 where it only regulates neurotransmitter release [50]. A2A activation causes increase in GABA release and re-uptake in hippocampus and glutamate release [51].

3.6.2 Heterodimers (figure 9)

Similar to A1 AR, A1A AR form heterodimers with dopamine receptors. More specifically, with D2-like DA receptors . As in the A1-D1 heterodimer, activation of either receptor in the A2A-D2 heterodimer leads to antagonism of the other receptor [52].

4. Mechanisms of Caffeine Addiction

4.1 Caffeine's addictive properties

Caffeine has addictive properties similar to classical psychostimulant drugs shown by experiments in animals’ discrimination experiments where caffeine and psychostimulant drugs can be interchanged with same resulting behavior [40]. Different classical psychostimulant drugs act through unique but converging molecular mechanisms with a final outcome of increased dopamine at the synapse [53]. They are considered to be indirect dopamine R agonists because don’t bind to the DR directly to increase dopamine release.

A study conducted by Myers and Izbicki in 2006 demonstrated low doses of caffeine are inherently reinforcing for rats not previously exposed to caffeine. The researchers observed rats had preference for sucrose with caffeine rather than sucrose by itself and this preference was not found to change (diminish) with time (suggesting there is no sensitization ). Conversely, high doses of caffeine were found to be aversive to rats but that aversive effect decreased over time. Thus, the study shows that some but not all of the properties of caffeine change with habitual use. Specifically, reinforcing properties of caffeine don’t change over time but aversion does (decreases).

4.2 Behavioral evidence for addictive properties of caffeine

The dopaminergic reward system is strongly implicated in addictive behaviors and motivation [54] . It islocalized primary in the nucleus accumbens which is part of the ventral striatum.
Dopamine agonists produce turning behavior and because caffeine consumption in mice can produce both dopamine-like and dopamine antagonist effects in turning behavior tests, it has been suggested caffeine can mimic direct and indirect dopamine agonist behavioral effects [55].

In addition, animals’ ability to distinguish caffeine from placebo is greatly decreased with dopamine depletion [56]. Thus, it can be concluded caffeine and the dopaminergic system are interacting at some level.

4.3 Caffeine and the dopaminergic reward system

Because the behavioral studies suggest caffeine interacts with dopamine and caffeine exerts its effects via adenosine R antagonism, there must exist an interaction between DR and AR. This is supported by evidence for heterodimerization between A1 AR-D1 and A2A AR-D2.

Non-specific adenosine receptor antagonists – caffeine and theophylline (found in tea) exert their stimulant effects via A2A and A1 receptors activation. A2A receptor has been studied with respect to possible addictive properties of caffeine as this subtype of adenosine receptor is densely expressed in the caudate and nucleus accumbens [57]. . However, so far the obtained results have been inconclusive and the interaction between adenosine and the reward system has not been confirmed. Therefore, it is still under debate whether caffeine can induce addiction.

4.4 Recent evidence for caffeine's non-addictive nature

Jessica E Sturgess et al published in 2010 a paper arguing caffeine administration does not increase dopamine transmission in the brain. This suggests caffeine might have an alternative (dopamine-independent) mechanism through which it exerts its rewarding effect but it also supports the hypothesis caffeine may not be an addictive substance.

Another study conducted by De Luca M.A. et al (2007)[58] argues that caffeine does not increase DA levels in the shell of the nucleus accumbens but in the near-by area of the medial prefrontal cortex. According to the authors, previous studies have come to wrong conclusions that caffeine causes increase of DA in the shell of nucleus accumbens due to imprecise probe placement. If this is the case, then caffeine does not cause the same neurotransmitter changes as classic psychostimulant drugs. Therefore, its addictive potential is challenged.

5. Tolerance Mechanisms

Physical dependence, or tolerance, is an important aspect of drug addiction. In this section, several hypothesis of the mechanisms of caffeine tolerance are discussed.

5.1 Tolerance demonstrated for some effects of caffeine

Tolerance in rodents has been confirmed for the following effects of caffeine:
- locomotor effects [59]
- subjective stimulant and anxiogenic side effects [60]

5.2 Tolerance through removal of withdrawal symptoms

One hypothesis for the development of caffeine dependence is that caffeine-seeking behavior is an attempt to alleviate the negative effects of caffeine withdrawal and therefore its indirect tolerance mechanisms is dependent on withdrawal [61]. More specifically, the positive (rewarding) effects of caffeine on performance and mood can be attributed almost exclusively to relief of withdrawal symptoms that occur shortly after abstinence of caffeine consumption. This is in contrast with the conclusions reach from the study conducted by Myers and Izbicki in 2006 where the authors concluded caffeine has inherently rewarding effects in rats independent of withdrawal. However, it must be noted the latter study’s results have not been confirmed with human subjects.

5.3 Evidence against the withdrawal hypothesis

A more recent study by Merideth Addicott et al (2009) [62] found caffeine causes small but significant cognitive and mood improvement in addition to alleviating withdrawal. This support the hypothesis caffeine has inherently rewarding effects.

5.4 Up-regulation of AR hypothesis

The original hypothesis for direct tolerance mechanisms of caffeine tolerance was that it is due to up-regulation of AR (increase in receptor numbers) [63]

5.5 Sensitization hypothesis

Holtzman et al (1991) [64] suggest a different explanation for caffeine tolerance. According to the authors, since caffeine is a competitive antagonist at the adenosine receptor, changes in the number of AR is theoretically irrelevant and the only important parameter is potency (binding affinity) of caffeine [65]. Indeed, in 1999 Fredholm et al reported habitual caffeine use leads to sensitization of A1 AR and down-regulation of beta-adrenergic receptors, the latter likely causing most of withdrawal symptoms.

Bibliography

1. Frary et al (2005) Food sources and intakes of caffeine in the diets of persons in the United States. J. Am. Diet. Assoc. 105, 110–113.

Neat topic choice, I'm sure many of us would self-identify as caffeine dependent. I would have expanded on the figures and added captions, but excellent visuals and thorough research, great job overall!

I enjoyed reading this! I agree that it's a very interesting and relevant topic. I think you could have gone a little more in depth in the pathways (as shown in the figures), but really interesting nonetheless!!

This is a really great page, I really enjoyed reading it. It's definitely a really relevant topic to our everyday lives, and I like the description of current hypotheses on how caffeine tolerance develops.

This is a great page with lots of images to add to its aesthetic appeal and to supplement understanding of the material. In terms of organization, I think it would have been better to have fewer subtopics with more content than more subtopics with less detail on each one. Overall, it's clear you put a lot of effort into researching this topic!

Probably one of the most relatable topics researched for this years neurowiki. There was good use of figures but perhaps it'd be better with some formatting with image size and placement. I'd have loved for some topics to have been elaborated on, but overall, super interesting neurowiki!

I liked the content of this page, but the visual organization was hard to follow. I found that some pictures were overly large and broke up the content, making the page harder to navigate. As an alternative, perhaps resizing the pictures to a smaller pixel size and allowing the user to click-to-enlarge would solve this problem. This can be done by editing the snippet code provided on the home page!